TARDBP

TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa), is a protein that in humans is encoded by the TARDBP gene.[5]

TARDBP
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTARDBP, ALS10, TDP-43, TAR DNA binding protein
External IDsOMIM: 605078 MGI: 2387629 HomoloGene: 7221 GeneCards: TARDBP
Gene location (Human)
Chr.Chromosome 1 (human)[1]
Band1p36.22Start11,012,344 bp[1]
End11,026,420 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

23435

230908

Ensembl

ENSG00000120948

ENSMUSG00000041459

UniProt

Q13148

Q921F2

RefSeq (mRNA)

NM_007375

RefSeq (protein)

NP_031401
NP_031401.1

Location (UCSC)Chr 1: 11.01 – 11.03 MbChr 4: 148.61 – 148.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal domain spanning residues 1-76 (NTD) with a well-defined fold that has been shown to form a dimer or oligomer;[6][7] 2 highly conserved folded RNA recognition motifs spanning residues 106-176 (RRM1) and 191-259 (RRM2), respectively, required to bind target RNA and DNA;[8] an unstructured C-terminal domain encompassing residues 274-414 (CTD), which contains a glycine-rich region, is involved in protein-protein interactions, and harbors most of the mutations associated with familial amyotrophic lateral sclerosis.[9]

The entire protein devoid of large solubilising tags has been recently purified.[10] The full-length protein is a dimer.[10] The dimer is formed due to a self-interaction between two NTD domains,[6][7] where the dimerisation can be propagated to form higher-order oligomers.[6]

The protein sequence also has a nuclear localization signal (NLS, residues 82–98), a nuclear export signal (NES residues 239–250) and 3 putative caspase-3 cleavage sites (residues 13, 89, 219).[10]

Function

TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. In particular, TDP-43 is a splicing factor binding to the intron8/exon9 junction of the CFTR gene and to the intron2/exon3 region of the apoA-II gene.[11] A similar pseudogene is present on chromosome 20.[12]

TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons.[13]

TDP-43 was originally identified as a transcriptional repressor that binds to chromosomally integrated trans-activation response element (TAR) DNA and represses HIV-1 transcription.[5] It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene.[14][15]

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.[16] It has also shown to be a neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.[17]

Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[18] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[19]

DNA repair

TDP-43 protein is a key element of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks (DSBs) in pluripotent stem cell-derived motor neurons.[20] TDP-43 is rapidly recruited to DSBs where it acts as a scaffold for the further recruitment of the XRCC4-DNA ligase protein complex that then acts to seal the DNA breaks. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients’ spinal cord specimens there is significant DSB accumulation and reduced levels of NHEJ.[20]

Clinical significance

A hyper-phosphorylated, ubiquitinated and cleaved form of TDP-43—known as pathologic TDP43—is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-TDP, previously referred to as FTLD-U[21]) and in amyotrophic lateral sclerosis (ALS).[22][23] Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, and has also been associated with ALS leading to the inference that athletes who have experienced multiple concussions and other types of head injury are at an increased risk for both encephalopathy and motor neuron disease (ALS).[24] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.[25] Misfolded TDP-43 is found in the brains of older adults over age 85 with limbic-predominant age-related TDP-43 encephalopathy, (LATE), a form of dementia.

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator "Tat" is dependent on an RNA regulatory element (TAR) located "downstream" (i.e. to-be transcribed at a later point in time) of the transcription initiation site.

Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[26] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[27][28][29] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[30] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[31] A recent study has demonstrated that cellular stress can trigger the abnormal cytoplasmic mislocalisation of TDP-43 in spinal motor neurons in vivo, providing insight into how TDP-43 pathology may develop in sporadic ALS patients.[32]

References
  1. GRCh38: Ensembl release 89: ENSG00000120948 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000041459 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Ou SH, Wu F, Harrich D, García-Martínez LF, Gaynor RB (June 1995). "Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs". Journal of Virology. 69 (6): 3584–96. PMC 189073. PMID 7745706.
  6. Afroz T, Hock EM, Ernst P, Foglieni C, Jambeau M, Gilhespy L, Laferriere F, Maniecka Z, Plückthun A, Mittl P, Paganetti P, Allain FH, Polymenidou M (June 2017). "Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation". Nature Communications. 8: 45. doi:10.1038/s41467-017-00062-0. PMC 5491494. PMID 28663553.
  7. Wang A, Conicella AE, Schmidt HB, Martin EW, Rhoads SN, Reeb AN, Nourse A, Ramirez Montero D, Ryan VH, Rohatgi R, Shewmaker F, Naik MT, Mittag T, Ayala YM, Fawzi NL (March 1, 2018). "A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing". EMBO Journal. 37: e97452. doi:10.15252/embj.201797452. PMC 5830921. PMID 29438978.
  8. Lukavsky PJ, Daujotyte D, Tollervey JR, Ule J, Stuani C, Buratti E, Baralle FE, Damberger FF, Allain FH (December 2013). "Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43". Nature Struct Mol Biol. 20: 1443. doi:10.1038/nsmb.2698. PMID 2424061.
  9. Conicella AE, Zerze GH, Mittal J, Fawzi NL (6 September 2016). "ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain". Structure. 24: 1537–49. doi:10.1016/j.str.2016.07.007. PMC 5014597. PMID 27545621.
  10. Vivoli Vega M, Nigro A, Luti S, Capitini C, Fani G, Gonnelli L, Boscaro F, Chiti F (October 2019). "Isolation and characterization of soluble human full-length TDP-43 associated with neurodegeneration". FASEB J. 33: 10780–93. doi:10.1096/fj.201900474R. PMID 31287959.
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  12. Gene Result
  13. Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J, Moore MJ, Yu G (January 2011). "Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes". The Journal of Biological Chemistry. 286 (2): 1204–15. doi:10.1074/jbc.M110.190884. PMC 3020728. PMID 21051541.
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  15. Mercado PA, Ayala YM, Romano M, Buratti E, Baralle FE (2005-10-12). "Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene". Nucleic Acids Research. 33 (18): 6000–10. doi:10.1093/nar/gki897. PMC 1270946. PMID 16254078.
  16. Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C (June 2007). "TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein". Molecular and Cellular Neurosciences. 35 (2): 320–7. doi:10.1016/j.mcn.2007.03.007. PMID 17481916.
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  29. Babić Leko, M; Župunski, V; Kirincich, J; Smilović, D; Hortobágyi, T; Hof, PR; Šimić, G (2019). "Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion". Behavioural Neurology. 2019: 2909168. doi:10.1155/2019/2909168. PMC 6350563. PMID 30774737.
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Further reading


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